Method of preparing 21-sulfonated steroids of the pregnane series



United States Patent 3,087,927 METHOD OF PREPARING ZI-SULFONATEDSTEROIDS OF THE PREGNANE SERIES Robert B. Brownfield, Spring Valley,N.Y., and Charles Krieger, Clifton, N.J., assignors to American CyanamidCompany, New York, N.Y., a corporation of Maine No Drawing. Filed July7, 1961, Ser. No. 122,413

7 Claims. (Cl. 260-23955) This invention relates to ZI-substitutedsteroids of the pregnane series. More particularly, it relates to 21substituted l6m,17a-dihydroxy pregnenes and pregnadienes.

The preparation of 2l-monoesters of steroids of the pregnane serieswhich initially contained reactive hydroxyl groups at C and C haspresented a ditiicult problem in the past. This was because of the factthat any esterification of l6a,l7a,2l-trihydroxy steroids resultedprimarily in l6a,2l-diesterification with small amounts of the 16m and2l-monoesterified steroids. The separation and purification of the2l-monoester has been found difficult, costly and time consuming.

It is well known that certain 2l-monoesters, notable themethanesulfonutes and p-toluenesulfonates, have found wide use asintermediates for the preparation of various pharmaceutically usefulZI-substituted steroids by virtue of their ability to undergo faciledisplacement reactions when treated with other nucleophiles. Forexample, 2l-alkyl (or aryl) sulfonated steroids can be readily convertedto the corresponding ZI-phosphorylated steroids either directly or viathe intermediate 21-halo steroids. Thus the availability of21-phosphorylated steroids, which are active glucocorticoids exhibitinghigh water solubility and good stability, is directly dependent upon theavailability of the corresponding 21-alkyl (or aryl) sulfonatedsteroids. While 2l-alkyl (or aryl) sulfonated derivatives of steroidscontaining only one reactive hydroxyl group (C are easily prepared byknown methods, the preparation and isolation of the correspondingderivatives of steroids containing more than one reactive hydroxyl group(e.g. C and C is accomplished only with extreme difficulty.

We have now found that 2l-alkyl (or aryl) sulfonated derivatives ofsteroids containing reactive hydroxyl groups at C and C can be preparedin good yield and with ease. We have also found that these 2l-alkyl (oraryl) sulfonated steroids can be converted by known methods to other2l-monosubstituted steroids in general and to 21-monophosphorylatedsteroids in particular as shown hereinafter.

The compounds prepared by the process of the present invention may beillustrated by the following formula:

CEIZOSOZR 3,087,927 Patented Apr. 30, 1963 wherein C -C is a divalentradical of the group consisting of CE: (IE2 and X is a monovalentradical of the group consisting of hydrogen and fluorine radicals, R isa member of the group consisting of H and 0: groups and R is a member ofthe group consisting of lower alkyl and mononuclear aryl radicals.

The starting materials utilizable in the process of the presentinvention can be, for example,

and the like.

Using the above steroids in a process illustrated in the flowsheethereinafter as (I and la) to (II and Ha), the 160:,170t-fllk0XYalkylidenedioxy derivatives of steroids of the pregnane series areprepared. The steroids described above are reacted with an ortho esterof the formula: R C(OR wherein R is hydrogen or lower alkyl and R islower alkyl. These compounds can be triethyl ortho formate, triethylortho acetate, trimethyl ortho propionate, trimethyl ortho acetate,trimethyl ortho formate and the like. The reaction to prepare thesteroids (II and Ha) of the flowsheet is carried out usually in thepresence of a mineral acid. The reaction will take place at atemperature within the range of from about 15 to about C. and is usuallycomplete in a period of from a few minutes to about an hour. As shown inthe flowsheet hereinafter, the structures of steroids (II) differdepending upon the degree of unsaturation in the A-ring.l,4-pregnadiene-3,20-diones (I) react with ortho esters to give steroids(II) in which the A-ring structure is unaltered. However,4-pregnene-3,20-diones (la) react With ortho esters to give steroids(Ila) in which ring A has been altered to a conjugated enol ether. SuchA-ring alterations, evident in the fiowsheet in steroids [Ila and Illa(described below)] do not influence the A-ring structure of the subjectsteroids (IV) since in the final step of the present invention (eg.steroids IIIa to IV) the original A-ring structure is regenerated byacid hydrolysis.

The preparation of the compounds illustrated in the flowshect as (IIIand Illa) takes place by reacting the compounds of (II and Ila) with alower alkyl sulfonyl halide or a mononuclear aryl sulfonyl halide. Thesesulfonyl halides may be, for example, methanesulfonyl chloride,benzenesulfouyl chloride, p-toluenesulfonyl chloride and the like.Usually it is desirable to carry out this reaction in a solvent whichacts as an acid acceptor, such as pyridine. Alternatively, the solventmay be, for example, dimethylformamide or dioxane along with an acidacceptor such as pyridine, triethylamine or the like. The reaction ispreferably carried out at a temperature within the range of from about20 C. to about 35 C. The reaction is usually complete in a few hours,however, the period may vary from about 2 to about 24 hours. The productis usually insoluble in water and it may be recovered by filtrationafter stirring the final reaction mixture into cold water.

The steroids illustrated by (IV) of the flowsheet are prepared from thesteroids of (III and Illa) by subjecting them to acid hydrolyticconditions to regenerate the viclnal cis-dihydroxy groups in the16a,l7a-positions and (in the case of parent 4-pregnene-3-ones) the A-3-one function in ring A. The hydrolysis may be carried out bydissolving the steroids of (III and Illa) in a solvent such aschloroform or methylene chloride containing a catalytic amount of amineral acid such as concentrated hydrochloric acid at a temperaturewithin the range of from about 25 to about 65 C. Under these conditionsthe reaction is complete in a period of from about one to about 24 hoursand the product, being insoluble in these relatively non-polar solvents,may be filtered directly from the reaction mixture or isolated by otherconventional means. Alternatively the steroids of (III and Illa) may besuspended in a solvent such as methanol and treated with an aqueousmineral acid such as dilute hydrochloric acid at a temperature in therange of about 25 to about 65 for a period of from about one hour toabout 24 hours. In practice, complete hydrolysis is effected by warmingthe methanolic reaction mixture to the reflux temperature for a periodof about one hour. The product steroids of (IV) may be isolated from thecooled reaction mixture by filtration either directly or after dilutionof the reaction mixture with Water. Frequently, it is not necessary topurify the steroids of III and Illa and the crude products are merelysubjected to the hydrolytic conditions to yield the final products (IV).

The following fiowsheet illustrates the various reactions of the presentinvention.

CHiY (i= I --o H R1: --orr X 01 C y Va. Y=I Vb. Y=o1 g on O-Na+ CIhOPCIIgOP (33:0 0-Na+ E O-Na+ --orr R1- OH R -OH 1. 1 C\ i 0 I r VI VIIo/orr or1,oP 0:0 OH

--OH R on R l I Ct IXa. R=N(C=Hs)a 1X0. B=HN NH in which R R R R and Xare as defined above. EXAMPLE I There has long been a need for a highlywater soluble form of a lfie-hydroxylated active steroid such astriamcinolone for pharmaceutical preparations. Steroid derivatives suchas borate salts and salts of half esters of steroids (e.g. the 2l-sodiumhemisuccinate) have been prepared in an effort to obtain such watersoluble forms, however, these forms have shown poor stabilitycharacteristics. On the other hand, ZI-phosphate esters of steroidswhich can be prepared, as shown in the flowshcet, from steroids (IV)have been found to be more stable and are superior as highly watersoluble forms. The process of the present invention for preparing 21-lower alkyl sulfonated and 2l-mononuclear aryl sulfonated steroidshaving 16e,l7a-dihydroxy groups thus provides a valuable means ofpreparing 2l-phosphate esters. As shown in the flowsheet, steroid2l-phosphnte esters and metal or amine salts thereof (VI-IXb) can beprepared either directly or by means of the corresponding 2l-halides (Vaand Vb).

The following examples describe in detail the preparation of 21-loweralkyl sulfonated and 2lmononuclear aryl sulfonated steroids of thepresent invention as well as the preparation therefrom of 2l-phosph-ateesters of 160z-hYdlOXYlBI6Cl steroids.

The ZLphosphate esters in the form of their metal or amine salts possesshigh water-solubility, high physiological activity and good stabilityproperties.

Preparation of 9a-F1u0r0-1IB-Hydr0xy-l 6a,] 7a-Mcthoxy- M ethoxymethylenedioxy-I ,4-Pregnadien -3,20-Di0ne The compound 9a-iluoro-11,8,16a,l7a,2l-tetrahydroxy- 1,4-pregnadiene-3,20-dione, 30 g. (76.1mmoles) is suspended in a solution made up of 300 ml. of reagent gradedioxane, 30.0 ml. (29.1 g., 274 mmoles) trimethyl orthoforrnate and 1.20ml. of absolute methanol. To the rapidly stirred (mechanical) suspensionthere is added dropwise 0.60 ml. concentrated sulfuric acid. Thesuspension thins continuously during the first few minutes and completesolution is effected within six minutes. Pyridine, 1.80 ml., is addedimmediately (if the reaction is allowed to proceed longer than thespecitied six minutes the solution becomes deep red and finally anopaque wine color. Quenching of the reaction mixture with pyridinebefore the red coloration develops has given the product in higher yieldand better initial purity) whereupon the faint pink coloration isdischarged and the resulting solution is light yellow in color. Theentire process to this point is carried out at room temperature. Thequenched reaction solution is placed in a separatory funnel, the stem ofwhich is immersed below the surface of three liters of a water-icemixture contained in a large beaker. The reaction mixture is addedslowly (over a period of 2 to 3 hours) to the vigorously agitatedice-water mixture. The white solid product which forms is allowed tostand in the aqueous solution at 5 C. overnight and then removed byfiltration. The product is finally washed well with water and air dried,28.7 g. (65.8 mmoles, 86.5%). On this scale the yields have ranged from69% to 87%. Several crystallizations from acetone-petroleum ether givesan analytical specimen of 9c: fiuoro 11 3,21 dihydroxy- 16ot,l7atmethoxymethylenedioxy 1,4 pregnadiene- 3,20-dione as colorlesscrystalline solid, melting point 2075-2085 C. (dec.) which ishomogeneous by paper chromatography (R 0.29) in the systemtoluenezpetro- Ieum ether (3060):methanolzwater (l.2:0.8:1.3:0.7); 111713, 1659 and 1618 CULT].

EXAMPLE II Preparation of 9ot-FIuro-1IB-Hydroxy-IMJ7u-Methoxymethylnedioxy 21 Merhanesulfonyioxy 1,4 Pregnadiene-3,20-Dione The compound9a-fiuoro-1lfi,21-dihydroxy-16ot,l7ctmethoxymethylenedioxy-l,4-pregnadiene-3,20-dione,9.63 g. (22.1 mmoles), is dissolved in 100 m1. of dry pyridine and thesolution is cooled in an ice-water bath. Methanesulfonyl chloride, 3.31g. (28.9 mmoles), is added slowly and with stirring to the cold pyridinesolution. The reaction mixture (a hazy solution) is stirred at ice-bathtemperature for one hour and then stored at l C. overnight. The reactionmixture is poured into ice water with stirring, the solid product isremoved by filtration, washed with water, 1.4 N hydrochloric acid (50ml.) and finally water-washed until the washes are neutral to litmuspaper. The air dried product amounts to 11.03 g., melting point2015-2025 C. (dec.). Refrigeration of the combined mother liquor andaqueous washes gives an additional 0.14 g. of solid. The total yield ofcrude product amounts to 11.17 g. (21.7 mmoles, 98.2%). An analyticalsample of 9a-fluoro-1lB-hydroxy 1601,1701 methoxymethylenedioxy 21methanesulfonyloxy-l,4-pregnadiene-3,20-dione as long, colorless needlesis obtained by repeated recrystallization from methanol, melting point2025-2035 C. (dec.); 11 1732, 1649, 1605, 1357 and 1174 cmr [a] +l14(c.=1.058, methyl Cellosolve, 1 dm.);

max.

EXAMPLE III To 9a-fluoro-11B-hydroxy-l6a,17a-rnethoxy methylenedioxy 21methanesulfonyloxy 1,4 pregnadiene- 3,20dione, 10.3 g. (20.0 mmoles), isadded 500 ml. of absolute methanol and 20.0 ml. of dilute hydrochloricacid is added. The stirred suspension is brought to reflux whereuponcomplete solution is effected. After about 20 minutes the solid beginsto separate and the amount of solid which separates during an additional20 minutes at refiux increases continuously (total reflux time 40minutes). The mixture is refrigerated overnight C.) and the solidproduct is removed by filtration. After washing with cold methanol andair drying, the product amounts to 8.27 g., melting point 198.0- 199.5(dec.). Concentration of the mother liquors gives an additional 0.61 g.of product as colorless solid. Combined crude yield-8.88 g. (18.8mmoles, 94.0%). Several crystallizations from methanol gives ananalytical specimen of9a-tluoro-l1p,16a,l7a-trihydroxy-2l-methanesulfonyloxy-1,4-pregnadiene-3,20-dioneas fine color less needles, melting point l97.0l97.5 C. (dec.); 1 1730,1660, 1618, 1340 and 1170 cmf M1 +54.8 (c.:0.803, methyl Cellosolve, 1dm.);

max.

8 EXAMPLE 1v Preparation of 9a-Flu0r0-1 16-Hydroxy-16a,17rx-Meth0xymetlzylenedioxy 21 p Toluenesulfonyloxy 1,4-Pregnot1iene-3,20-Dione Using the process described in Example 11 andsubstituting p-toluenesulfonyl chloride for methanesulfonyl chloride,the above identified Steroid is obtained in good yield, p 1730, 1660,1613, 1361 and 1177 CDT-1.

EXAMPLE V Preparation of 9a-F uor0-11816a,]7a-Trihydroxy-21-p-Tolucnesulfonyloxy-I,4-Pregnadiene-3,20Di0ne The product of Example IV,9a-fiuoro-llti-hydroxy- 160:,17a methoxymethylenedioxy 21 p toluencsulfonyloxy-1,4-pregnadicne-3,20-dione, is heated with absolute methanoland dilute hydrochloric acid as described in Example 111. The desiredtrihydroxy steroid is obtained in good yield, melting point 181-182 C.(ClC.);1/ 1725, 1659, 1603, 1370 and 1178 cmf EXAMPLE VI Preparation of3-Methoxy-11,B,21-Dihydroxy-I6u,17a-Methoxymet/1ylenedioxy-3,5-Pregnadiene-ZO-One The compound11;9,16a,l7u,21-tetrahydroxy-4-pregnone-3,20-dione, 1.00 g., is reactedwith trimethyl orthoformate by the method of Example I to give 0.87 g.of 3-methoxy-1lfl,2l dihydroxy-16a,l7amethoxymethylene-dioxy-3,5-pregnadiene-20-one. An analytical sampleshowed a melting point of 176-177 C.; 11 1715, 1657, 1631 and 1170 crnfEXAMPLE VII Preparation of 3-Methoxy-1lfi Hydroxy-l6u,I7a-Mellzoxymethyienedioxy-ZI-Methanesulfonyloxy3,5-Pregnndiene-ZO-One.

The compound3-methoxy-115,2l-dihydroxy-16a,l7amethoxymethylenedioxy-3,S-pregnadiene-ZO-one,0.36 g., is treated with methanesulfonyl chloride by the method ofExample II to give 0.29 g. of 3-n1ethoxy-l1 fi-hydroxy- 160:,17amethoxymethylenedioxy-2l methanesulfonyloxy-3,S-pregnadiene-ZO-one; u1725, 1650, 1348 and 1170 cm:'

EXAMPLE VIII Preparation of 9a-Flu0ro-21-Hydr0xy-I6a,17a-Methoxymethylenedioxy 1 ,4-Pregnadiene-3,11 ,ZO-Trione The compound9a-fluoro 16a,l7u,21-trihydroxy-l,4- pregnadiene-3,11,20-trione isreacted with trimethyl orthoformate according to the method of Example Ito give L-flUOI'O'21-hydI'OXy-l6d,17d methoxymethylenedioxy- 1,4-pregnadiene-3,1 1,20-trione.

EXAMPLE X Preparation of 9a-Flu0ro t,17a Methoxymethylenedioxy21Methanesulfonyloxy-I,4 Pregnadt'ene-3,I1, ZO-Trione The compound9a-iluoro-2lhydroxy-l6u,l7a-methoxymethylenedioxy-l,4-pregnadiene-3,11,20-trione isreacted with methanesulfonyl chloride according to the method of ExampleII to give 9a-iluoro-l6ot,17a-methoxymethylenedioxy-Zlmethanesulfonyloxy- 1,4-pregnadiene-3,l1,20-trione.

9 EXAMPLE XI Preparation of 9tl-FIMOrO-16a,17mDihydroxy-ZI-Methanesulfonyloxy-I ,4-Pregnadiene-3,11 ,ZO-Trione Thecompound 9u-fiuoro-16a,17a-methoxymethylenedioxy-Zlmethanesulfonyloxy-l,4 pregnadiene-3,11,20- trione is hydrolyzed inabsolute methanol with dilute hydrochloric acid according to the methodof Example III to give 9m-fluoro16u,17a-dihydroxy-2l-methanesulfonyloxy-l,4-pregnadiene-3,1 1,20-trione.

EXAMPLE XII Preparation of 3-Methoxy-21-Hydroxy-16a,17a-Methoxymethylenedioxy-3,5-Pregnadiene-20-One The compound16a,1711,21-trihydroxy4-pregnene-3,20- dione is reacted with trimethylorthoformate according to the method of Example I to give3-methoxy-2l-hydroxy- 160:,l7a. methoxymethylenedioxy3,5-pregnadiene-20- one.

EXAMPLE XIII Preparation of S-Metizoxy-IMJ 7a-Methoxymethylene dioxy-21-M ethanesul fortyloxy-S ,5 -Pregnadiene-20-One The compound3-methoxy-16a,17a-methoxymethylenedioxy-Zl-hydroxy-3,5-pregnadiene-20-oneis treated with methanesulfonyl chloride in pyridine according to themethod of Example II to give a3-methoxy-l6a,l7u-methoxymethylenedioxy-Zl-methanesulfonyloxy3,5-prcgnadiene-20-one.

EXAMPLE XIV Preparation of 16a,17a-Dihydroxy-21-Methaneszzlfonylxy-4-Pregnene-3,ZO-Dione The compound3-methoxy-16,1'Za-methoxymethylenedioXy-21 methanesulfonyloxy-3,5pregnadiene-ZO-one in absolute methanol is hydrolyzed with dilutehydrochloric acid according to the method of Example 111 to give160:,17ot-Clll'lYdl0XY-Zl methanesulfonyloxyA-preg nene-3,20-dione.

EXAMPLE XV Preparation of 21Jodo-S wFluoro-l118,16a,1 7 u-Trihydroxy-I,4-Pregnadiene-3,20-Dione The compound 9ot-fiuoro-llti,l6e,l7atrihydroxy-21- methanesulfonyloxy-1,4 pregnadiene-3,20-dione, 6.50 g.(13.8 mmoles), is suspended in 300 ml. of acetone. Sodium iodide, 3.25g. (21.7 mmoles) is dissolved in 200 ml. of acetone and the solution isadded with stirring to the steroid suspension. The stirred mixture isrefluxed for one hour and minutes during which time the suspension thinsconsiderably but at no time is complete solution effected. The hotmixture is filtered, the solid (Water soluble-sodium methanesulfonate)is washed with hot acetone and the combined filtrates are refrigeratedovernight. The first crop of long, fine colorless needles is removed byfiltration, washed with cold acetone and finally air dried, 1.62 g.,melting point 170.5-1710" (dec.). A second crop of colorless solid isobtained by concentration of the combined mother liquors and washes,5.26 g., melting point 169170 (dec.). The yield is 6.83 g. (13.6 mmoles,99.1%). Repeated recrystallization from acetone-petroleum ether (boilingpoint 60-70") gives an analytical specimen of 2l-iodo-9u-fluoro-llfi,l6a,17oi-trihydroxy-1,4 pregnadiene-3,20dione, melting point 1750-1760C. (deo, with violet vapor filling to tube spontaneously at 172); p1695, 1650, 1597, 1068 and 892 MIL-1; [a] +87 (c.:0.586, Dis 1F, 1 dm.);

iltll 239 E =17, 100

10 EXAMPLE XVI Preparation of 21-Chloro-9a-FIuoro-11,3,16:1,1711-Trihydroxy-1,4-Pregnadiene-3,20-Dione The compound Qm-flllfll'O-l 1pt,l6e,l7a-trihydroxy-2lmethanesulfonyloxy-1,4-pregnadiene-3, 20-dione(0.75 g.), lithium chloride (202 mg.) and dimethylformarnide (30 ml.) isrefluxed for 50 minutes, concentrated under reduced pressure to a smallvolume and treated With water. The solid so obtained is separated byfiltration and recrystallized from acetone-petroleum ether (boilingpoint 60-70") and from isopropanol; weight 278 mg, melting point 26l-263dec. The sample for analysis is obtained by recrystallization frommethanol which lowers the melting point to 250-251 dec.; A 239 m (e15,300); r 3330, i739, 1678, 1627 and 1610 cur- []D25+83 (dioxane).

In other runs it was found that the reflux time may be successfullyshortened to 8 minutes or that the reaction mixture may be simplystirred at room temperature for 45 minutes.

EXAMPLE XVII Preparation of 9oi-Fluor0-11 8,16a,I 7a,2l'-Tetrahydroxy-1,4-Pregnadiene-3,20-Dione 21 Sodium Hydrogen Phosphate Phospohric acid(15.6 ml, and trisilver phosphate (41.5 g.) are combined with coolingand intimately mixed to form a paste. Acetonitrile, 260 ml., is addedand to the stirred suspension is added 25.0 g. of 21-iodo-9a-fiuoro-1lpi,l6a,l7e,trihydroxy 1,4 pregnadiene-Ia,20- dione andfinally an additional 160 ml. of acetonitrile.

, The mixture is heated at reflux temperature for 4 hours,

cooled to room temperature and finally filtered through diatomaceousearth to remove insoluble solids. The filter cake is washed withmethanol and the combined filtrates are treated batchwise with asulfonic acid cation exchange resin (H+ cycle) until the solution isfree of silver ion and exhibits an apparent pH of about 2. The solutionis passed slowly through a column of a Weakly basic ion exchange resin(0%? cycle) which treatment effectively removes inorganic phosphate ionsfrom the methanolacetonitrile solution of steroid phosphate. Thesolution is adjusted to pH 5.2 with a 2% solution of sodium methoxide(total volume2530 ml). The solution is evaporated to a small volumeunder reduced pressure, diluted with ether and the resultant suspensionis refrigerated overnight. The product is collected by filtration,washed with ether and air dried to give 20.0 g. of 9oi-fluoro-l lit,l6a,17e,2 ltetrahydroxy-1,4-pregnadiene 3,20 dione-2lsodium-hydrogenphosphate. Qualitative paper strip chromatography in the systemisopropanol/conc. am monium hydroxide/water (7:122) indicates tracecontaminants of non-phosphorylated steroids at R 0.35 and no inorganicphosphate contaminants (R 0.08). The major component(steroid-2l-phosphate) appears as a strong spot at R 0.45.

EXAMPLE XVIII Preparation of 9a-Fll1or0-I I 8,160:,17a,2l-Tcrmllydrox)-1 ,4-Pregnadien e-3,20-Di0ne-21 S dium Hydrogen Phosphoto The compound2l-chloro-9a-lluoro-ll5,l6a,17a-trihydroxy-l,4-pregnadiene-3,20-dione istreated with 85% phosphoric acid and trisilver phosphate according tothe method of Example XVII to give the monosodium salt of fluoro-ll;3,l6a,l7n,2l-tetrahydroXy-l,4-pregnadi ene-3,20-dione-2lphosphate ofpurity comparable to that of the product of Example XVII. R; 0.45[system isopropanol/conc. ammonium hydroxide/water (7:1:2)].

1 1 EXAMPLE XIX Preparation of 9a-Fl'uoro-11,3,]6a,17a.21-Tctm/zydr0.ry-1 ,4-Prcgnadiene-3,20-Dione-21 -Trierhy[ammonium H ydrogen Phosphate Theproduct of Example XVII (impure monosodium salt of9a,fluoro-11B,16a,17a,21-tetrahydroxy-1,4-pregnadiene-3,20-dione-2l-phosphate),4.98 g., is taken up in 70 ml. of the lower phase of the system N/lammonium hydroxide-n-butanot and extracted with four small portions ofthe upper phase of the same two-phase system. The aqueous, ammoniacalsteroid solution is treated batchwise with a sultonic acid ion exchangeresin (H+ cycle) until the solution shows a constant pH of about 2. Thesolution is then treated batchwise with a sulfonic acid ion exchangeresin [HN(C H cycle] until the solution is pH 4.2 and constant. Thesolution is flushed with nitrogen under reduced pressure to removedissolved n-butanol and is finally freeze dried to give 3.61 g. of themono triethylarnmonium salt of 9u-fiuoro-11fi,16o ,l7a,Zl-tetrahydroxy-l,4-pregnadiene-3,20-dione-2l-phosphate as colorlesssolid, melting point 163170 (dec.);

Preparation of 9ut-Flzi0r0-11flJ6txJ 7a,21 -Terrahydro.ry-1,4-Pregnadiene-3,20-Df0ne-2J -D1's0dium Phosphate The product ofExample XVII (impure monosodium salt of9a-fluoro-11p.16a,170:,2l-tetrahydroxy-1,4pregnadiene-3,20-dione-2l-phosphate)10 g., is taken up in 250 ml. of the lower phase of the system N/lOammonium hydroxide-n-butanol and the resulting solution is extractedwith several small portions of the upper (butanol) phase of the samesystem. This treatment eflectively removes nonphosphorylated steroidcontaminants. The solution, pH 9.25, is treated (columnwise) with asulfonic acid ion exchange resin (Na cycle) until the solution exhibitsa constant pH of about 11. The pH of the solution is then lowered toabout 6 by batchwise treatment with a sulfonic acid ion exchange resin(H' cycle). At this point the dissolved steroid phosphate exists as amix ture of the monoand disodium salts uncontaminated with excessammonium hydroxide, sodium hydroxide and nonphosphorylated steroid. Thesolution is titrated to pH 8.25 (the pH of the steroid-Zl-phosphatedisodium salt) with a dilute solution of sodium hydroxide. The solutionis flushed with nitrogen under reduced pressure to remove dissolvedbutanol and then freeze dried to give 9.20 g. of hydrated9a-fiuoro-11fl,16a,17m,2l-tetrahydroxy-l,4-pregnadiene-3,20-dione-2l-disodiumphosphate as colorless solid. Paper chromatography in the systemisopropanol/conc. ammonium hydroxide/water (7:1:2) showed a single spot,R 0.45. Solubility of the product in water is in excess of 600 mg/ml.

EXAMPLE XXI Preparation of 9a-Flu0r0-I 1,6,16a,1 70121 -Tetrahydroxy-1,4-Pregnadiene-3,20-Dione-2I -Dihydr0gen Phosphate The product ofExample XX (hydrated 90c fiuoro 11B, 16a,17u,21 tetrahydroxy 1,4pregnadiene 3,20- dione 21 disodium phosphate), in absolute methanol, istreated batchwise with a sulfonic acid ion exchange resin (H+ cycle). Asmall aliquot of this solution when diluted with water shows a pH of2.6. The methanolic solution of the steroid-2l-dihydrogenphosphate isevaporated to dryness under reduced pressure. The residue iscrystallized by slow evaporation in a concentrated acetone solution. Thecrystalline product is recrystallized from acetone (tracemethanol)-petroleum ether (6040") to give hydrated9a-fluoro-llfl,l6a,17a,2l-tetrahydroxy-1,4-pregnadiene-3,20-dione-2l-dihydrogen phosphate as colorless crystallinesolid. Paper chromatography in the system isopropanol/conc. ammoniumhydroxide/water (721:2) showed a single spot, R 0.45.

EXAMPLE XXlI Preparation of 9e-FInor0-I 1 3,16 7a,2I-Tetrahydr0xy- 1,4-Prcgnadiene-.i,20-Dions-Zl-Plrosplmre, Piperazz'ne Salt The product ofExample XX (hydrated 911 fluoro- 1lt3,16a,17 z,2l tetrahydroxy 1,4pregnadiene 3,20- dione 2l disodium phosphate), 1.00 g., is dissolved in8 ml. of water and the solution is adjusted to pH 8.5 with dilutedsodium hydroxide solution. The resulting solution is added with stirringto 15 ml. of a hot aqueous solution containing 1.00 g. of pipcrazinediacetate. The white solid which forms almost immediately is filteredfrom the hot solution, Washed with water then methanol and is finallyair dried. A second crop is collected, washed and dried in the samemanner, total yield 0.83 g. Vacuum drying at 56 for 6 hours gives themonohydrate of fiuoro 1l 8,16a,17a.21 tetrahydroxy 1,4 pregnadiene 3,20dione 21 phosphate, piperazine salt, melting point 240 (dec);

We claim:

1. A method of preparing compounds of the formula:

crnosorm wherein --C C is a divalent radical of the group consisting of/Cgz (in:

CII and (1311 X is a monovalent radical of the group consisting ofhydrogen and fluorine radicals, R is a member of the group consisting ofin which R is a member of the group consisting of hydrogen and loweralkyl radicals and R is a lower alkyl radical to produce compounds ofthe formula:

ClIzOII 13 wherein R R R and X are as defined above and -C C C C -C C isa radical of the group consisting of CH CH2 CH CH:

I E and Lower I & 0:C\ C\ alkyl-OG CH CH2 CH C6 reacting the lattercompounds with a member of the group consisting of lower alkylsulfonylhalides and mono nuclear arylsulfonyl halides to produce compounds ofthe formula:

CIIzOSOzR wherein X is a monovalent radical of the group consisting ofhydrogen and fluorine radicals, R is a member of the group consisting of11 and 0 groups and R is a member of the group consisting of lower alkyland mononuclear aryl radicals which comprises reacting compound of theformula:

CIIQOH R and X are as defined above, R is a member of the groupconsisting of hydrogen and lower alkyl radicals, R is a lower alkylradical with a compound of the group consisting of lower alkylsulfonylhalides and mononuclear Cal 14 arylsulfonyl halides to produce compoundsof the formula:

CH OSOR X tower ammo-Q's wherein R R R R and X are as defined above,hydrolyzing the latter steroids at least 40 minutes with a mineral acidin the presence of a solvent inert to the reactants and recovering saidcompound therefrom.

4. A process of preparing compounds of the formula:

wherein R is a member of the group consisting of CHzOSOzR H and groups,X is a monovalent radical of the group consisting of hydrogen andfluorine radicals and R is a member of the group consisting of loweralkyl and mononuclear aryl radicals which comprises reacting compoundsof the formula:

CH OH wherein R and X are as defined above, R is a member of the groupconsisting of hydrogen and lower alkyl radicats and R is a lower alkylradical with a compound of the group consisting of lower alkylsulfonylhalides and mononuclear arylsulfonyl halides to produce compounds of theformula:

OH OSOgR is O/ \m 04 13 wherein R R R R- and X are as defined above,hydrolyzing the latter steroid with a mineral acid in the presence of asolvent inert to the reactants and recovering said compound therefrom.

5. A process of preparing 1lfi,160:,17a-ttii13d1'0XY-21-methanesulfonyloxy-4-pregnene-3,ZO-dione which comprises reacting 3methoxy 11 8,21 dihydroxy 16a, 17a-methoxymethylenedioxy 3,5 pregnadiene20 one with methanesulfonyl chloride to produce B-methoxy-llflhydroxy1604,17; methoxymethylenedioxy 21 methanesulfonyloxy 3,5 pregnadiene 2 0one, subsequently hydrolyzing with a mineral acid in the presence of asolvent inert to the reactants and recovering said compound therefrom.

6. A process of preparing 9a-fiuoro-11fl,16a,17m-trihydroxy 21methanesulfonyloxy 1,4 pregnadiene 3, ZO-dione which comprises reacting9ot-fiuoro-11B,21-dihydroxy 160:,170: methoxymethylenedioxy 1,4"-pregnadiene-3,20-dione with methanesulfonyl chloride to pro duce 9afluoro 115 hydroxy 1601,17: methoxymethylenedioxy 21 methanesulfonyloxy1,4 pregnadiene-3,20-dione, subsequently hydrolyzing with a mineral acidin the presence of a solvent inert to the reactants and recovering saidcompound therefrom.

7. A process of preparing 9a-fiuoro-11B,16ot,17a-trihydroxy 21 ptoluenesulfonyloxy 1,4 pregnadiene- 3,20-dione which comprises reacting9a-fluOrO 11fi,2l-di- References Cited in the file of this patent UNITEDSTATES PATENTS 2,903,449 Fried et al. Sept. 8, 1959 2,949,476 Tyner Aug.16, 1960 2,966,486 Smith et a1. Dec. 27, 1960 OTHER REFERENCES Smith etaL: J.A.C.S., 82, September 5, 1960, pages 4625-2629.

1. A METHOD OF PREPARING COMPOUNDS OF THE FORMULA:
 2. THE COMPOUND3-METHOXY-11B-HYDROXY-16A,17A-METHOXYMETHYLENEDIOXY-21-METHANESULFONYLOXY3,5-PREGNADIENE-20-ONE.